Journal of Hypertension 2 0 09

1. Reappraisal ofEuropean guidelines on hypertension management: aEuropean Society of HypertensionTask Force document Journal of Hypertension 2009

2. Authors/Task Force Members: Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ, Cifkova R, Clément D, Coca A, Dominiczak A,Erdine S, Fagard R, Farsang C, Grassi G, Haller H, Heagerty A, Kjeldsen SE, Kiowski W, Mallion JM, Manolis A, Narkiewicz K, Nilsson P, Olsen MH, Rahn KH, Redon J, Rodicio J, Ruilope L, Schmieder RE, Struijker-Boudier HA, van Zwieten PA, Viigimaa M, Zanchetti A Journal of Hypertension 2009

3. European Guidelines Purpose of European guidelines is to be educational and not prescriptive or coercive for the management of individual patients who may differ widely in their personal, medical and cultural characteristics, thus requiring decisions different from the average ones recommended by (many) guidelines

4. Questions Posed by Recent Trials • Beneficial effects of BP reduction on systolic / diastolic heart failure particularly if entry BP is below or only slightly above 140/80 mmHg (TRANSCEND / PROFESS / I-PRESERVE) • Small / non significant effects of antihypertensive treatment, even if BP lowering effect is marked, on dementia (HYVET) • Negative findings on secondary prevention of AF by ARBs in specifically-designed trials (CAPRAF / GISSI-AF) • Negative findings on primary prevention of AF by ARBs (TRANSCEND / PROFESS) • Use of low dose aspirin in diabetes

5. BP Goal(s) • Sufficient evidence to recommend that SBP be lowered to< 140/90 in both low-moderate and high risk HTs • Evidence missing in the elderly (benefits of lowering SBP to< 140 mmHg never tested in randomized trials) • Considering additional (weaker) evidence it may be prudent to recommend lowering BP within the 130-139/80-85 mmHg range in all HTs, and possibly close to lower values in this range • More critical evidence from specific randomized trials desirable

6. Treatment Initiation at High Normal BP (130-139/85-89 mmHg) • If no diabetes / previous CV events no trial evidence of treatment benefits (except of delayed new HT) • No prospective trial evidence also in diabetes - treatment recommended if organ damage (particularly renal) is present • Trial evidence in patients with previous CV events controversial - further trials to be completed before firm recommendation can be given

7. Initiation of Drug Treatment • Prompt drug treatment in grade 2/3 HT • Reasonable to make use of drug treatment also in grade 1 HT, although no trial evidence in grade I hypertensives at mild / moderate risk • Recommendation to start drug treatment at BP≥ 140/90 mmHg in the elderly as well although evidence mainly based on • “Post-hoc” event data • Improvement of organ damage • Delayed treatment leads to irreversible organ damage / greater residual risk

8. Choice of Antihypertensive Drugs (I) • Large scale meta-analyses do not confirm the contention that major antihypertensive drug classes differ significantly for their ability to reduce BP • There is also no undisputable evidence that major drug classes differ in their ability to protect against overall CV risk or cause-specific CV events, e.g. stroke and myocardial infarction • The 2007 ESH/ESC guidelines conclusion that D / ACEI / CA / ARB / BB can all be considered suitable for initiation / maintenance of antihypertensive treatment can thus be confirmed

9. Choice of Antihypertensive Drugs (II) • The percentage of patients responsive to any drug class is limited • Patients responsive to one drug are often not those responsive to another drug • Thus keeping the number of drug options large increases the chance of BP control in a larger fraction of HTs • This is of crucial importance because CV protection by antihypertensive treatment substantially depends on BP lowering per se, regardless of how it is obtained

10. Choice of Antihypertensive Drugs (III) • Each drug class has contraindications as well favourable effects in specific clinical settings. The choice of drugs should be made according to this evidence • The traditional ranking of drugs into first / second / third and subsequent choice, with an average patient as reference, has now little scientific and practical justification and should be avoided

11. Ranking Drugs in Order of Choice • Any all-purpose ranking of antihypertensive drugs for general antihypertensive usage is unnecessary and probably deceiving • Even reasons based on costs, often used to justify ranking, have recently been weakened by the advent of generic compounds within every class of antihypertensive agents

12. 2007 ESH/ESC Hypertension GuidelinesFirst Choice Drug Treatment • Diuretics* • ACE-inhibitors • Calcium antagonists • Angiotensin receptor antagonists • Beta-blockers* * not to be initially preferred in patients at high risk of developing diabetes

13. New Meta-analyses from Old andMore Recent Trials • New trials demonstrating the protective effects of one or another drug class within the five classes selected as first choice options • Substantial equivalence of protective effects of different drug classes for similar BP reductions

14. BP Reduction and CV Protection • BP reduction per se plays a major role in CV and renal protection of hypertensive patients • The greater the number of available therapeutic options to lower BP the better

15. Fixed-dose (or Single Tablet) Combinations • Guidelines have long favoured the use of two-drug combinations in a single tablet(improvement in compliance which is low in hypertension) • Whenever possible, use of single tabletcombinations should be preferred, because simplification of treatment carries advantages for compliance to treatment • Single tabletcombination can be the first treatment step when high CV risk makes early BP control desirable • This approach is now facilitated by the availability of different fixed-dose combinations of the same two drugs

16. Choice of Combinations • Despite trial evidence of outcome reduction, the BB / diuretic combination favours development of diabetes and should thus be avoided, unless required for other reasons, in predisposed subjects • Use of an ACEI / ARB combination presents a dubious potentiation of benefits with a consistent increase of serious side effects • Specific benefits in nephropathic patients with proteinuria (because of a superior antiproteinuric effect) expect confirmation in event based trials

17. Choice of Combinations • Several drug combinations are suitable for clinical use • Trial evidence of outcome reduction has been obtained particularly for the combination of - Diuretic + ACEI - Diuretic + ARB - Diuretic + CA - ACEI + CA • The ARB + CA combination also appears to be rational and effective • These combinations should thus be recommended for priority use

18. Combination Therapy (I) • Evidence has continued to show that in the vast majority of HTs effective BP control can only be achieved by combination of at least two antihypertensive drugs • Addition of a drug from another class to the initially prescribed one should thus be regarded as a recommendable treatment strategy, unless the initial drug needs to be withdrawn because of the appearance of side effects or the absence of any BP lowering effect

19. Combination Therapy (II) The two drug combination may offer advantages also for treatment initiation, particularly in high CV risk patients in whom early BP control may be desirable Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment

20. Combination Treatment • New and old evidence strongly suggests combination treatment as the most effective strategy to control BP • Treatment strategies should be largely based on the addition of a drug from another class to the initially prescribed one whenever BP control is not achieved (unless the starting drug needs to be changed because of side effects or the absence of any BP reduction)

21. Combination Therapy • Evidence has continued to show that in the vast majority of HTs effective BP control can only be achieved by combination of at least two antihypertensive drugs • Addition of a drug from another class to the initially prescribed one should thus be regarded as a recommendable treatment strategy, unless the initial drug needs to be withdrawn because of the appearance of side effects or the absence of any BP lowering effect

22. Combination Therapy • The two drug combination may offer advantages also for treatment initiation, particularly in high CV risk patients in whom early BP control may be desirable • Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment

23. Fixed Combinations • Whenever possible, use of fixed dose (or single pill) combinations should be preferred, because simplification of treatment carries advantages for compliance to treatment

24. Preferred Combinations (I) • Outcome reduction has been documented for combinations such as - ACEI / D - ARB / D - CA / D - ACEI / CA

25. Preferred Combinations (II) • The ARB/CA combination has several potential advantages (effective BP reduction / high rate of BP control / highly favourable tolerability profile / protection against organ damage). It has never been tested / widely used in outcome trials, except for RENAAL (together with D)

26. Preferred Combinations (III) • Successful outcome trials have also used the BB/D combination, which however more easily induces new onset diabetes in predisposed subjects • New evidence warns against the ARB/ACEI combination (dubious additional benefits but more frequent serious side effects) at least in high risk patients

27. ACEI / D ARB / D ACEI / CA CA / D CA / BB ARB / CA Combinations Tested or Widely Used in Outcome (CV-renal events) Trials PROGRESS ADVANCE HYVET LIFE SCOPE RENAAL Syst-Eur Syst-China INVEST ASCOT HOT ACCOMPLISH FEVER ELSA VALUE HOT (2nd used) RENAAL (with D as well)

28. Three Drug Combinations • In no less than 15-20% of HTs BP control cannot be achieved by a two drug combination • When three drugs are required, the most rational combination appears to be a RAS blocker, a calcium antagonist and a diuretic at effective doses

29. Beta-blocker / Diuretic Combination • Despite trial evidence of outcome reduction, the BB / diuretic combination favours development of diabetes and should thus be avoided, unless required for other reasons, in predisposed subjects

30. ACEI / ARB Combination • An ACEI / ARB combination presents a dubious potentiation of benefits with a consistent increase of serious side effects • Specific benefits in nephropathic patients with proteinuria (because of a superior antiproteinuric effect) expect confirmation in event based trials

31. ACEI / CA Combination • Tested or widely used combination therapy inSyst-Eur / Syst-China / HOT / ASCOT / INVEST / ACCOMPLISH • Greater CV protection than placebo in Syst-Eur / Syst-China • Equal (INVEST) or greater (ASCOT) CV protection than D/BB • Greater CV protection than ACEI/D in ACCOMPLISH

32. ARB / CA Combination • The ARB/CA combination presents with several advantages - Effective BP reduction - High rate of BP control - Highly favourable tolerance profile (better than the ACEI / CA combination) - Protection against organ damage • However, it has never been tested / widely used in outcome trials • An exception is RENAAL in which nephroprotection by ARB was seen on a background of common treatment with CA (but also D)

33. Fixed-dose (or Single Pill) Combinations • Guidelines have long favoured the use of two-drug combinations in a single tablet (improvement in compliance which is low in hypertension) • Single tablet combination can be the first treatment step when high CV risk makes early BP control desirable • This approach is now facilitated by the availability of different fixed-dose combinations of the same two drugs

34. Combinations of More than Two Drugs • No less than 15%-20% of the patients need more than two antihypertensive drugs to achieve an effective BP reduction • The combination of a RAS blocker, a CA and a thiazide may be a rational three drug combination • Other drugs such as -blockers or an -blocker may be included in this multiple approach, depending on the clinical circumstances

35. Subclinical OD in Total CV Risk Quantification (I) • In HT assessment of total CV risk it is important to optimize decision about treatment initiation / intensity / goals • Quantification of total CV risk mustinclude search for subclinical OD, which is common and has independent prognostic significance • In HTs the presence of subclinical OD usually brings CV risk into the high range • Subclinical OD may not be sufficient to bring NTs into the high risk category, although this may occur with multiple OD and the metabolic syndrome

36. Subclinical OD in Total CV Risk Quantification (II) • Several measures of renal, cardiac and vascular damage can be considered for total CV risk quantification • Because of their simplicity, wide availability and limited cost measures based on urinary protein excretion (including microalbuminuria), eGFR (MDRD formula), and EKGare suitable for routine use

37. Subclinical OD in Total CV Risk Quantification (III) Cardiac and vascular ultrasounds are more and more easily available in Europe, and their use in the evaluation of the hypertensive patient can be encouraged Subclinical OD should be assessed both at screening and during treatment because a number of treatment-induced changes in OD relate to CV and renal outcomes, thereby offering information on whether the selected treatment is protecting patients

38. Subclinical OD in Total CV Risk Quantification (IV) • Several other measures of subclinical OD have been shown to have prognostic significance, but their complexity / low availability and high cost prevent their routine clinical use • It is likely that technological progress will make the use of some of these measurements more common in the future • Any measure, however, should be considered only if it adds to the overall precision of CV risk quantification

39. Subclinical Organ Damage as a Marker ofHigh CV Risk Condition in Patients Study Tsioufis Mihani CASE-J trial CV Health Study ELSA Laurent Fowkes De Buyzere Koren Tsioufis HOT INSIGHT Jensen Condition Hypertension Outpatients Hypertension Elderly Hypertension Hypertension Outpatients Outpatients Hypertension Hypertension Hypertension Hypertension Hypertension Organ damage LVH (echo) LVH (echo) LVH (echo)  Ca IMT (highest quintile)  Ca IMT (2 highest quintiles) PWV (highest quintile)  Ankle / brachial ratio  Ankle / brachial ratio LVH (echo) Low eGFR Low eGFR or high SCR (≥ 1.5 mg/dl) Low eGFR or high SCR (≥ 1.5 mg/dl) MA 10 yr CVD ≥ 20% Yes Yes Yes Yes Yes Yes Yes (men) Yes (men) Yes Yes Yes Yes Yes (CHD)

40. Threshold / Target BP for Treatment in DM • Antihypertensive treatment to be always initiated when BP ≥ 140/90 mmHg • Limited trial support for treatment initiation at high normal BP / to be recommended in the presence of organ damage (e.g. microalbuminuria) • The < 130/80 BP goal not supported by trial evidence / very difficult to achieve • Realistic to pursue a sizeable BP reduction without indicating a goal which is unproven

41. Antihypertensive Drugs in Diabetics • Meta-analyses of available trials show that in diabetes all major antihypertensive drug classes protect against CV complications, probably because of the protective effect of BP lowering per se. They can thus all be considered for treatment • In diabetes combination treatment is commonly needed to effectively lower BP • A renin angiotensin receptor blocker should always be included because of the evidence of its superior protective effect against initiation or progression of nephropathy

42. Antihypertensive Treatment in DM • All major antihypertensive drugs are protective • Combination treatment is commonly needed • A RAS blocker should always be included because of superior protection against appearance / progression of nephropathy

43. Blood Glucose Control in Diabetics • In hypertensive diabetic patients tight blood glucose control (HbA1C to 6.5%) is beneficial, particularly in microvascular complications • Recent evidence suggests that combining effective blood glucose and BP control increases protection, particularly of the kidney • Tight blood glucose control should not be pursued abruptly and patients should be monitored closely because of the increased risk of severe hypoglycaemic episodes

44. Microvascular Complications • Microvascular complications of diabetes in different organs are differently affected by treatment • Antihypertensive treatment exerts a major protective effect against renal complications, while evidence of a similar effect on eye and neural complications is less consistent

45. New Antihypertensive Drugs • No donors • Vasopressin antagonists • Neutral endopeptidase inhibitors • AT2 receptor agonists • Endothelin receptor antagonists • Renin inhibitors

46. Antihypertensive Treatment in the Elderly (I) • In the elderly antihypertensive treatment is highly beneficial (large meta-analyses) • In patients aged ≥ 65 the proportional benefit is no less than in younger patients • Data (large meta-analyses) do not support the claim that antihypertensive drug classes significantly differ in their ability to lower BP / exert CVprotection both in younger and in elderly patients • The choice of the drugs to employ should thus not be guided by age • Thiazide diuretics / ACEIs / CA / ARBs / BBs can be considered for initiation / maintenance of treatment also in the elderly

47. Antihypertensive Treatment in the Elderly (II) • In the elderly outcome trials have only addressed patients with an entry SBP > 160 mmHg • In no trial in which a benefit was achieved SBP averaged< 140 mmHg • Common sense considerations suggest that also in the elderly drug treatment can be initiated when SBP > 140 mmHg with the goal of going below this value • Treatment should be conducted with particular attention to adverse responses, potentially more frequent in the elderly

48. Treatment in Patients Aged ≥ 80 Years • Evidence is now available from an outcome trial (HYVET) that antihypertensive treatment has benefits also in patients aged 80 years or more • BP lowering drugs should thus be continued or initiated when patients turn 80, starting with monotherapy and adding a second drug if needed • Because HYVET patients were generally in good condition, the extent to which HYVET data can be extrapolated to more fragile octogenarians is uncertain • The decision to treat should thus be taken on an individual basis, and patients should always be carefully monitored during and beyond the treatment titration phase

49. New Trials Needed - Trial Design • Grade 1 HT / low-moderate risk  placebo-controlled trial / intermediate endpoints • Elderly / grade 1 HT (goal < 140/90 mmHg)  placebo-controlled trial / hard CV outcomes • DM or previous CVD / high normal BP (Goal < 130/80 mmHg)  placebo-controlled trial / hard CV outcomes • Lowest safe BP values with treatment  More vs less intense BP lowering treatment in patients with different CV risk levels • Lifestyle measures in HT  Controlled randomized trial / intermediate endpoints in patients with grade I HT or high normal BP

50. New Trials Needed • Should antihypertensive drug treatment be prescribed in grade 1 HT (BP 140-159 / 90-99 mmHg) when total CV risk is low-moderate? • Should antihypertensive drugs be prescribed in the elderly with grade 1 HT with the goal to go < 140/90 mmHg? • Should antihypertensive drugs be started when BP is in the high normal range in diabetics / patients with CVD history with the goal to go < 130/80 mmHg? • What are the lowest safe BP values to achieve in different clinical conditions? • Are lifestyle measures known to reduce BP capable of reducing morbidity / mortality in HT?